Aflatoxin: a cancer-causing glue
In our previous blog post, we announced our Aflatoxin Challenge – a new series of Foldit puzzles designed to tackle a common poison known as aflatoxin. This week, Baker Lab scientist ianh offers a more detailed picture of the chemistry behind aflatoxin's harmful effects.
Most people on Earth consume aflatoxins every day. Aflatoxins are compounds produced by certain fungi that can grow in or on almost all grains and groundnuts. Aflatoxins are known hepatocarcinogens, meaning they cause liver cancer in high doses. Liver cancer is the third leading cause of cancer death globally, with 83% of cases occurring in East Asia and sub-Saharan Africa where aflatoxin exposure is highest.
What makes aflatoxin so toxic?
Surprisingly, aflatoxin itself isn’t toxic. Once ingested, our body uses its normal metabolic processes to try to break it down. It turns out a metabolic product of aflatoxin – not aflatoxin itself – is harmful, and the chemistry behind its toxicity is both frightening and familiar.
One of the metabolic enzymes that acts on aflatoxin is CYP3A4, a vitally import liver enzyme tasked with breaking down different complex molecules. Its normal targets are molecules produced by our own bodies, like the sex hormones testosterone and estrogen, but CYP3A4 can also safely chew up some of the complex chemicals we put in our body, such as caffeine (found in coffee and tea) and lidocaine (a local anesthetic commonly used by dentists).
When CYP3A4 metabolizes a chemical it changes that molecule’s structure in some way. When it acts on aflatoxin, it adds a chemical feature – chemists call this new feature an epoxide group.
Epoxide groups are highly reactive, meaning they are unstable on their own and like to bond with other nearby chemicals. This extreme reactivity can be harnessed for many practical applications, including adhesion, electrical insulation, and industrial manufacturing. Some of the strongest glues ever made – epoxy glues – are based on epoxide chemistry.
Once CYP3A4 converts aflatoxin into epoxy-aflatoxin, the compound doesn’t wait around for long. It quickly reacts with other chemicals in our cells, especially amines.
One of the best places to find amines in our cells in our DNA. Each of the four letters of DNA – A, T, G, and C – is an amine. Epoxy-aflatoxin reacts especially strongly with guanosine (G), forming a nearly-unbreakable bond. This permanently damages DNA.
DNA damage is problematic, not only because it interferes with the natural processes of the damaged cell, but because this damage can be passed on to descendants when the damaged cell replicates. In this way, a single error in a single cell may be amplified over time to affect a large population of cells.
The liver is especially prone to this cascade because it (1) expresses high levels of the CYP3A4 protein that metabolizes aflatoxin, and (2) because liver cells reproduce at faster rates than cells of other organs, allowing DNA mutations to accumulate and propagate much more quickly.
Human DNA includes a gene that encodes for the tumor-suppressing protein p53. The normal role of the p53 protein is to police DNA damage in the cell. It recognizes DNA damage and can initiate DNA repair processes or, in extreme cases, induce cell death. Without functional p53 protein, DNA damage runs rampant in a cell. Dysfunctional p53 is strongly associated with many forms of cancer in humans.
It seems that one particular guanosine in the p53 gene is especially susceptible to aflatoxin damage. Damage to this guanosine is propagated to descendant cells as a G -> T mutation in the p53 gene; the G -> T mutation in the p53 gene results in a ARG -> SER mutation in the p53 protein. The p53 protein falls victim to the very type of DNA damage it is meant to avert! This mutated version of p53 is exceedingly common in liver cancer patients.
In summary: aflatoxin causes DNA damage in the liver, resulting in a population of cells with defective p53 and prompting tumor growth.
Help us design a protein to break down this toxic compound by playing the latest Foldit puzzle, 1445: Aflatoxin Challenge: Round 2 with Insertions!( Posted by ianh 76 2091 | Tue, 10/31/2017 - 17:26 | 1 comment )